Integrins are intimately involved in a diversity of biological processes and are proven therapeutic targets for several diseases. Talin binding to integrin has been demonstrated to be the common final step in integrin activation, but the signaling mechanisms by which regulates integrin activation are unknown. It has been reported that talin undergo rapid phosphorylation accompanying focal adhesion disassembly when fibroblasts are exposed to stimuli, but the roles of talin phosphorylation are unclear. This proposal aims to identify the talin phosphorylation sites and the responsible protein kinases in vitro and in vivo, to examine the role of talin phosphorylation in cell migration, focal adhesion dynamics, and integrin activation, and to dissect the molecular mechanism. The results from the proposed experiments will provide valuable insights into the molecular mechanisms for regulating integrin activation. The identified protein kinases responsible for talin phosphorylation will be potential therapeutic targets.